1. Field of the Invention
The invention is on the compositions and uses of the extract [350-450 Dalton molecular weight fraction] from the annatto seed and such extract that is annatto oil or oleoresin containing non-saponifiables, especially non-saponifiable terpenoids.
2. Description of the Related Art
Tocotrienols generally are classified as farnesylated chromanols (FC) and mixed terpenoids. Tocopherol and tocotrienol are believed to have beneficial effects because they act as antioxidants. Tocotrienols, in particular, have been documented to possess hypocholesterolemic effects, as well as, an ability to reduce atherogenic apolipoprotein B and lipoprotein plasma levels. Further, tocotrienols are believed to be useful in the treatment of cardiovascular disease and cancer (Theriault, A., et al., 1999; Watkins, T. et al., 1999). Delta-tocotrienol and gamma-tocotrienol, in particular, have been identified as effective suppressants of cholesterol activity (Qureshi, A., et al., 1995), and in inducing apoptosis of breast cancer cells (Yu, W. et al., 1999).
Tocols, which includes tocopherols and tocotrienols, have several sources, including several vegetable oils, such as rice bran, soybean, corn and palm. However, each source of tocotrienols and tocopherols generally contains more than a single tocol homolog. For example, palm oil and rice bran oil generally include both tocotrienols and tocopherols. Further, alpha-tocopherol has been reported to attenuate certain effects of tocotrienols, such as the cholesterol-suppressive activity of gamma-tocotrienol (Qureshi, A., et al., supra.). In addition, because of their structural similarity, tocotrienols and tocopherols can be difficult to separate.
Tocotrienols (including delta- and gamma-tocotrienols) and geranyl geraniols have been discovered in the seeds of Bixa orellana Linn, otherwise known as the achiote tree. It is a member of the Bixaceae family and is native to tropical America. It is grown commercially in other parts of the world, generally within 20° of the equator or more preferably within 15° of the equator.
The seeds of Bixa orellana are the source of a reddish-orange colorant, known as annatto, that contains bixin and orelline, both of which are carotenoid pigments. The colorant is used commonly in foods, dyes and polishes. Typically, annatto is extracted from dehusked seeds in an aqueous caustic solution. The colorant is precipitated from the aqueous solution by addition of acid, and the precipitated colorant is removed by filtration. The oily phase is usually separated from the aqueous solution, and discarded as a byproducts.
A “byproduct solution of Bixa orellana seed components” is defined herein as a solution derived from Bixa orellana seed components having a concentration of annatto colorant significantly reduced from that of Bixa orellana seeds themselves. Other common terms for byproduct solution used for commercial products include: oil-soluble annatto color, annatto oil, annatto oleoresin, or annatto extract.
Annatto extracts contain predominantly tocotrienols, geranyl geraniols, bixins and to a lesser extent components of oleoresinous materials, of which all these major and minor components (both saponifiables and non-saponifiables) are unique to annatto extracts. These extracts can be used as a nutritional supplement, nutraceutical, functional food and beverage, animal ingredient and pharmaceutical, or as an admixture with other natural extracts [350-450 Dalton molecular weight fraction] or nutrients.
Vitamin E constitutes a class of tocochromanols containing at least four tocopherols and at least four tocotrienols. “Toco” means birth, “pheren” to bring forth, “triene” three double bonds, “ol” alcohol, and “chroman” the attached ring structure. The chroman alcohol has consistently indicated that all E vitamers are powerful membrane-soluble antioxidants (Serbinova, E., et al., 1991; Yoshida, Y., et al., 2003). The “triene” refers to the 3 double-bonded tail in a tocotrienol which differentiates it from a tocopherol's saturated tail. The “triene” tail (also referred to as farnesyl tail) is about a third shorter than the saturated tail (also referred to as phytyl tail). These vitamin E tocochromanols include the lesser abundant tocodienols (“diene” with two double-bonded tail) and tocomonoenols (“monoene” with one double-bonded tail). The Greek alphabets “alpha”, “beta”, “gamma” and “delta” refer to the degree of methyl substitutions in the chroman structure (Table 1).
TABLE 1Molecular weightsTocopherolTocotrienolAlpha430424Beta417411Gamma417410Delta403396
Vitamin E, including tocopherols and tocotrienols, are typically 390-430 Daltons in molecular weight or more broadly 350-450 Daltons in molecular weight, which includes tocopherols and tocotrienols without any methylated groups in the lower range and tocopherols and tocotrienols with fully methylated groups in the higher range.
The reason for the antioxidant scavenging efficiency of tocotrienol (T3) is because of its shorter farnesyl tail. The farnesylated tail enables the tocotrienol to move with superior mobility across cell membranes, giving rise to greater efficiency in free-radical scavenging activity (Serbinova, E. et al., 1991; Packer, L., et al., 2001). The longer phytyl tail of the tocopherol (T1), which anchors deeply into lipid membranes, renders tocopherol less mobile and thereby making it less efficient as a scavenger than T3.
The farnesol tail is required to reduce cholesterol. Farnesol down regulates, as well as, degrades HMG CoA reductase, the enzyme that controls cholesterol biosynthesis. It is believed that the farnesyl tail of tocotrienol works by this mechanism (Pearce, B., et al., 1992), a possibility that does not exist with tocopherol. Fully occupied methyl substitution on the chromanol (e.g., alpha isomer) prohibits any reaction and unoccupied substitution on the ring (e.g., delta isomer) makes available reactive nitrogen oxide trapping capability (Jiang, Q., et al., 2001). As shown in FIG. 2, when the carbon position 5 is unoccupied, T1 or T3 becomes “C-5 unsubstituted”.
Tocotrienol contains three repeating isoprene units giving rise to the farnesyl tail. Geranyl geraniols (GG), both cis and trans isomers, contain four isoprene repeating units and surprisingly the tocotrienol farnesyl moiety is contained in the GG tail, and therefore GG is believed to be an unique component in the annatto extract, among other valuable components. In fact, the entire GG molecule is contained in and used for the biosynthesis of a tocotrienol molecule where one of the four isoprene moieties is embedded inside the T3 chroman ring (Elson, C., et al., 1995; Cahoon, E., et al., 2003; Dormann, P., 2003). See FIG. 2. Hence, both GG and tocotrienol structures have a common moiety, farnesyl group, which is believed to modulate biological activities including some overlapping activities. Annatto carotenoids (with conjugated double bonds) of various chain lengths and existing as non-oxygenated carotenes, oxygenated xanthophylls, such as free alcohols, acids, aldehydes, ketones, esterified or etherified with other annatto extract components are inclusive of the said extracts, and of this invention.
FIG. 1 shows the tocols compositions from different natural sources are highly varied, which argues for the standardization of tocols to produce an “appropriate spectrum” to address appropriate diseases and conditions, a concept that surprisingly has not been implemented. Annatto extract contains tocols that are consistent, typically 90% delta-T3 and 10% gamma-T3. The rationale for the use of tocotrienol containing annatto seed lipids is to increase the in vivo and ex vivo biological activities of these admixtures, and to increase the biological potency of these admixtures by decreasing the amount of alpha-T1 consumed. Alpha-tocopherol has been shown to interfere with tocotrienol's ability to sequester cholesterol biosynthesis (Qureshi, A., et al., 1996) and alpha-T1 has no effect on anticancer activity (Guthrie, N., et al., 1997; Yu, W., et al., 1999). Large doses of alpha-T1 has produced a marked hypertriglyceridemic effect in animals (Khor, H. and T. Ng, 2000; Lehman, J., 1981) and in humans (Farrell, P. and J. Bieri, 1975; Tsai, A. et, al., 1978). Consequently, the increase of delta-T3 and/or gamma-T3 presents superior biological and antioxidant properties vis-à-vis alpha-T1.
Table 2 shows a non-exhaustive sample of diverse health benefits and protection of the eight classically and individually known E vitamers. A need exists to develop a rationale for an “appropriate spectrum” tocols product that would normalize and/or optimize biologic functions without the crossover mitigation of tocopherols. To date, only “full spectrum” tocols (implied presence of all eight tocols) are commercially available, espousing to deliver the composite health benefits of the individualized effects of those found in Table 2. It remains unsubstantiated that full-spectrum tocols will deliver the complete effects of these individually identified properties. Therefore, these full-spectrum tocols lack a compositional, technical and/or scientific basis or rationale. Currently, no present art teaches compositions and methods of use in humans, nor teaching so efficaciously and by simply adding natural tocols extracts in appropriate combinations.
TABLE 2Isolated uses and effects of individual tocopherols and tocotrienols.Alpha-tocopherolHigh abundance in sun flower and cotton seeds. Highest Vitamin Eactivity, Vitamin E claims in food/supplement systems. High levels ofalpha-T1 mitigate effects of tocotrienols.Beta-tocopherolLow abundance in plants (found in wheat germ).Gamma-tocopherolHigh abundance in soy and corn. Nitrogen dioxide scavenging (smokingdetoxification), natriuretic. High levels of alpha-T1 inhibit gamma-T1absorptionDelta-tocopherolAbundance in soy and wheat germ. Both delta-T1 and gamma-T1 areantioxidants in food systems (as mixed tocopherols in preserving foods),both trap RNOSAlpha-tocotrienolAbundance in rice and palm. Powerful anti-oxidant compared to alpha-T1(40-60X in some biologic systems). First discovered to reduce cholesterol,but is a weak reducer. Inhibits neurotoxicity; cell signaling; skindeposition.Beta-tocotrienolLow abundance in plants (found in wheat germ). Not a significantbiologic contributor with effect same as alpha-T3 or unknown.Gamma-tocotrienolHigh abundance in rice, palm, and annatto. Natriuretic and inhibitscancer, atherosclerosis, osteoporosis, cholesterol, and hypertension.Delta-tocotrienolHigh abundance in annatto. The most active component amongtocotrienols. Biologic activity: 1-2 times greater than gamma-T3 and 4-10times greater than alpha-T3. Delta-T3 repairs nerve damage and inhibitsinflammatory stimuli, cholesterol, and cancer.
It is generally desirable to target diseases with specific isomers of tocols. For example, to lower lipids, it is desirable to have the highest levels of delta-T3 and gamma-T3 and lowest levels of tocopherols, especially alpha-T1 (Qureshi, A., et al., 1996). Such compositional specificity which is required to lower cholesterol is presently unattainable. Table 3 presents the natural compositional abundance typically found in plant sources. The natural abundance of palm and rice sources favors relatively large amounts of alpha-T3 and gamma-T3, as well as, large amounts of tocopherols. Consequently, the disclosed use of palm and rice TRFs to lower lipids has limited utility. This is because these TRFs are high in alpha-T3, low or absence in delta-T3 and high in tocopherols (30-50%), especially alpha-T1. Such compositional variability in TRF fractions have been responsible for several equivocal clinical study outcomes (Mustad, V., et al., 2002; Mensink, R., et al. 1999).
Soy and corn oils contain exclusively tocopherols, although they tend to be highest in the C5 unsubstituted tocopherols (70-90% as delta-T1 and gamma-T1) (see, Sheppard, A. et al., 1993). Such high levels of C5 unsubstituted delta-T1 and gamma-T1 from soy and corn (Table 3) have unique admixture application, which unexpectedly have not been implemented.
TABLE 3Compositional abundance of tocotrienols in various plantsource materials.TocotrienolsTocopherols(% wt TRF)(% wt TRF)Source of materialAlphaGammaDeltaAlphaGammaDeltaAnnatto oil1<0.110.090.0<0.1NDNDPalm oil226.527.99.027.6ND9.0Rice bran oil324.719.41.144.98.51.3Rice bran oil47.040.20.732.617.62.0Wheat germ oil50.9NDND47.79.39.7Soy oil6NDNDND6.670.123.4Corn oil6NDNDND15.082.52.5ND, not detected1DeltaGold ®, annatto derived tocotrienol concentrate, product of American River Nutrition, Inc.2TRF concentrate from palm oil (Indonesian & Malaysian origin).3TRF concentrate from rice bran oil (Japanese origin).4TRF concentrate from rice bran oil (Thailand origin).5Contains 6.5% beta-T3 and 26% beta-T1.6Sheppard et al. (1993); corn may contain traces of T3.
The effectiveness of cholesterol reduction is due to the farnesylated tail of tocotrienols where the isomeric potency of delta-T3 is greater than gamma-T3, and in turn is five-fold greater than alpha-T3 (Pearce, B., et al., 1992). Furthermore, cholesterol reduction is mitigated by tocopherols, especially alpha-T1.
It is known that the structural isomeric form of tocols (either tocopherols or tocotrienols) that confers the greatest potency has no substitution in the carbon-5 (C5) position (Jiang, Q., et al., 2001; Qureshi, A., et al., 1995; McIntyre, B., et al., 2000). FIG. 2 shows that C5 unsubstituted positions are delta and gamma isomeric forms and that C5 substituted (or occupied) positions are alpha and beta isomeric forms. Hence, delta-T3 and gamma-T3 are the most active tocotrienols, and delta-T1 and gamma-T1 are the most active tocopherols. Put together, annatto extracts can be defined as tocopherol-free and have the highest potency tocotrienols that can be combined with other tocols contained in the 350-450 Dalton molecular weight fraction of natural extracts to produce an “appropriate spectrum” tocols.
Cell line studies have predicted that delta-T3 and gamma-T3 behave synergistically, and other TRFs contain a large proportion of alpha-T3 which have no synergistic role to other tocotrienols (Pearce, B., et al., 1992). However, these aspects have never been proven in clinical studies.
Insulin Resistance
The origin of diabetes is due to defects in insulin secretion and/or action. However, it is very difficult to separate over production of insulin (hyperinsulinemia, HI) from dysfunction of insulin itself (insulin resistance, IR). It has been argued that HI and IR necessarily coexist into a form of aberrant metabolic control (Chen, Y. and G. Reaven, 1998). Alternatively, it is also reasoned that the pathogenesis of diabetes initiated with an insulin secretion defect that led to insulin dysfunction (DeFronzo, R., 1998). Regardless of the etiology of IR, the pancreatic beta cell will respond to IR by increasing insulin secretion to offset the insulin action defect. This compensatory HI will down regulate insulin action further and create a circular perpetuation of IR. Thus the plasma insulin response will become progressively impaired and pancreatic beta cell exhaustion will eventuate. Because of these circular events leading to IR, overt diabetics are frequently on insulin medication. Clinically and epidemiologically, IR (a prediabetes state), and not insulin level, marks the progression to diabetes.
Insulin resistance (IR) is associated with increased risk of cardiovascular disease (CVD), Type 2 diabetes mellitus (T2DM), hypertension, polycystic ovarian syndrome (PCOS) and alcohol-unrelated fatty liver disease. However, plasma insulin measurement is not standardized across clinical laboratories, and therefore is an unreliable marker. Therefore, a surrogate marker was developed for insulin resistance, where the IR criteria are TG/HDL≧3.5 and/or TG≧140 mg/dL (McLaughlin, T., et al. 2003).
Inflammation
The process(es) of inflammation can explain numerous underlying mechanisms of cancer, degenerative disease, atherosclerosis and thrombosis (arterial clogging), and indeed global inflammation processes themselves (e.g., acute and chronic inflammation, autoimmune diseases, joint pain and rheumatoid arthritis). It is known that tocotrienols reduce certain inflammatory markers, such as, thromboxane (TXB4), prostaglandin E2 (PGE2), platelet aggregation, tumor necrosis factor (TNF) and nuclear factor kappa B (NFkB) (Qureshi, A., et al., 2002, 2001, & 1997; Qureshi, A. and D. Peterson, 2001; Watkins, T., et al., 1999; Tomeo, A., et al., 1995; Kooyenga, D. et al., 2001; Ahn et al., 2007). There is a possible role of inflammatory proteins on prediabetic condition, especially of IR. Subjects with IR had higher VCAM-1, CRP, IL-6 and TNFα (Deepa, R., et al., 2003; Rekeneire, N., et al., 2003; Festa, A., et al., 2003).
Cardiovascular Disease
Cardiovascular disease has been differentiated into low, intermediate and high risk categories (Ridker, P., et al., 2003). The study indicated that the individuals with the lowest CVD risk were subjects with the lowest CRP and without IR. Conversely, the study showed that the individuals with the highest CVD risk were subjects with the highest CRP and with IR. Put together, annatto C5 unsubstituted T3 reduce IR and CRP, and therefore reduce prediabetic conditions of IR, diabetes, and especially diabetic and non-diabetic CVD.
Cardiovascular disease and T2DM have shared common antecedents of metabolic events and processes. They are diseases of chronic dysfunction of the microvascular and macrovascular systems, and vaso-endothelial dysfunction of the endocrine system (Liao, J., 1998). Molecular processes often involve oxidative stresses, production of bioactive materials, leading to inflammation processes. For example C-reactive protein, a bioactive material, is a sensitive marker of inflammation.
Inflammation processes in the vasculature have been widely reviewed (Jenkins, A. and T. Lyons, 2000; Prescott, S., et al., 2001; Sylvester P. and A. Theriault, 2003). Gamma-tocopherol (gamma-T1) and gamma-T3 upregulate endothelial nitric oxide synthase, and these two C5 unsubstituted gamma isomers are important in preventing vascular and endothelial dysfunction (Carr, A. and B. Frei, 2000; Newaz, M., et al., 2003) and that delta-T3 followed by gamma-T3 markedly inhibit bioactive materials, namely VCAM-1 and E-selectin (Chao, J., et al., 2002). This is especially relevant because these endothelial dysfunction markers (E-selectin, ICAM-1 and VCAM-1) predict T2DM, and are independent precursors of T2DM (Meigs, J., et al., 2003). Therefore, the C5 unsubstituted tocols are uniquely suited to inhibit bioactive materials orchestrated by inflammatory stimuli and prevent the tethering of circulating monocytes and leukocytes onto endothelial cells. The break of this restraint onto the circulating cells by the C5 unsubstituted tocols is one critical intervention in protecting the integrity of the vasculature, and therefore atherosclerosis.
HDL is well known for its role in circulating cholesterol back to the liver. Moreover, the HDL particles (“good cholesterol”) have anti-inflammatory and anti-thrombotic properties and suppress surface bioactive materials, as well as, markedly inhibit oxidized LDL formation and NFkB activation (Robbesyn, F., et al., 2003; Jenkins, A. and T. Lyons, 2000).
Lipidemia and Diabetic Dyslipidemia
Tocotrienols have been used for treatment of lipidemia and diabetic dyslipidemia, through tocotrienol inhibition of hepatic cholesterol biosynthesis, specifically via the inhibition of HMGR, the rate limiting step in cholesterol synthesis. However, diabetes represents a plethora of pathological events besides cholesterol dysfunction where T3 has not been represented to work, especially the C5 unsubstituted tocols. Sterol regulatory element binding protein-1 (SREBP-1) is a transcription factor that responds to nutritional status and regulates metabolic gene expression in various organs, including liver, adipose and muscle. It has been shown that insulin and glucose induced de novo fatty acid synthesis leading to a rapid increase in lipogenic flux in skeletal muscle. Such lipid accumulation is associated with muscle IR in obesity and T2DM, and is stimulated/mediated via the SREBP-1 expression (Guillet-Deniau, I., et al., 2003). As discussed earlier, IR is tightly associated with increased lipids (McLaughlin, T., et al., 2003) and increased insulin or HI (DeFronzo, R., 1998).
Diabetes
Diabetes may be considered a hypercoagulable state. Diabetic platelets are hypersensitive to platelet aggregating agents, and the vasoconstrictor TXB4 is a powerful platelet aggregator. Excess TXB4 release in diabetics has been associated with CVD in these patients. These matters have been well documented and is herein referenced in its entirety (Colwell, J., 1997 & 2004). Aspirin specifically blocks the omega-6 arachidonic acid-derived thromboxane TXB4 synthesis, which dramatically reduces platelet aggregation, and has been used as a primary and secondary strategy to prevent cardiovascular events in patients. Aspirin's major risks are gastric mucosal injury, G.I. hemorrhage and hemorrhagic stroke (Colwell, J., 1997 & 2004). It is known that gamma-T3, delta-T3 and gamma-T1 inhibit platelet aggregation, TXB4 and PGE2 (Qureshi, A., et al., 2002; Saldeen, T., et al., 1999) and that delta-T3 preferentially absorbs onto circulating human platelets (Hayes, K., et al., 1993). Gamma-T3 and gamma-T1 both metabolize in mammalian tissues to gamma-carboxyethyl hydroxy chromans (γ-CEHC), essentially the chromanol ring without the farnesyl and phytyl tails. It has been shown that their parent moieties, as well as, the γ-CEHC metabolite inhibit PGE2 and COX2 (Jiang, Q. et al., 2001) which further supports that C5 unsubstituted tocols play a role in inhibition of vasoconstriction, coagulation/clotting, and chemotaxis. Therefore, C5 unsubstituted tocols should help to reverse the hypercoagulable state of diabetes in a safe manner without side effects.
Diabetes is a disease of frank hyperglycemia and the control of sugar is always a standing goal. It is now recognized that glycation of lipids and proteins contributes to diabetic macrovascular and microvascular diseases. For example, glycoxidized LDLs increased binding to extracellular matrix, have procoagulant effects, extravasate into glomeruli, retinae and atheroma. Also glycoxidized albumin adheres to the aortic wall. According to one research study, there was an approximately 6-fold accumulation of glycoxidized N-(carboxymethyl) lysine (CML) in the hearts of diabetic patients as compared to normal subjects (Schalkwijk, C., et al., 2003). Other advanced glycation end-products (AGE) including Amadori modified proteins, all of which are sugar-mediated oxidation to proteins are herein referenced by way of examples (Jaleel, A., et al., 2003; Araki, Y., et al., 2003; Szwergold, B., et al., 2003). The measurement of glycated hemoglobin (HbA1c) in the blood is a standard marker to measure the history of sugar damage to tissues. Tocotrienols, especially gamma-T3 inhibit protein oxidation (Kamat, J., et al., 1997). Further, tocotrienols effectively prevented an increase in AGE in normal rats, and decreased blood glucose and HbA1c in diabetic rats (Nazaimoon, W. and B. Khalid, 2002).
Peroxisomal Proliferator Activated Receptor
Peroxisomal proliferator activated receptors (PPAR) are members of the nuclear receptor transcription factors. The metabolic consequences of PPARγ activation have been mostly researched on adipose tissue where it is largely expressed (Smith, S., 1998; Kraegen, E., 1998). The metabolic effects of thiazolidinediones (TZD) are: a) reduce hyperglycemia and hyperinsulinemia, b) lower FFA and TG levels, c) enhance IS and lower IR states, and d) use insulin to lower glucose. TZD are known PPARγ agonists or activators. Many of PPARγ activator functions are similar to PPARα activator functions. PPARα has been actively researched on liver tissue, especially with regards to lipid use (e.g., uptake and beta-oxidation). Even though the action sites of PPARγ (predominantly in adipose) and PPARα (mainly in liver) are different, their activations have many overlapping clinical outcomes. Typically TZD and fibrates affect the activation of PPARγ and PPARα, respectively. Tocotrienols in this invention behave primarily like a TZD (and secondarily like a fibrate) as T3 metabolic effects match those four listed above for TZD. Surprisingly, the chromanol ring structure found in T3 is the same moiety found in troglitazone, a TZD. Put together, C5 unsubstituted T3 activate or agonize the nuclear transcription factor PPAR (γ, α, or mixed) and thereby carry out the metabolic effects similar to those of TZDs and fibrates, in many common tissue sites (adipose, skeletal muscle, and kidney, macrophage, VSMC, endothelial cell) and different sites for PPARγ (heart, gut) and PPARα (liver). These various PPAR expressions share more common sites than different ones. Mixed PPAR activation, besides PPARγ and PPARα, also includes PPARδ whose expression is ubiquitous in all tissues.
Nervous System
Reversing damage to the neurons and brain, whether acute or chronic is an important health issue. Potential neuropotent nutrients have to address the issue of the blood brain barrier (BBB), over which the nutrients must cross over to enter the brain. All tocotrienols enter the brain in general, and they protect glutamate-induced neurotoxicity (Sen, C., et al., 2000). As well, these C5 unsubstituted tocols, both tocotrienols (McIntyre, B., et al., 2000) and tocopherols (Liu, M., et al., 2002) have particular bioavailability into cellular tissues. Brain cells are typically rich in PUFAs, especially the omega-3 DHA and EPA, and hence they are very susceptible to oxidation. In studies with brain mitochondrial organelles, tocotrienols and TRF effectively prevented oxidative damages to both lipids, as well as, proteins. Studies of brain mitochondria and rat microsomes indicate gamma-T3 is the most effective in oxidative protection followed by alpha-T3 and delta-T3 (Kamat, J. and T. Devasagayam, 1995; Kamat, J., et al., 1997). The gamma-T1 is mostly located in the biomembranes of brain homogenates, and it markedly inhibits lipid peroxidation in the brain (Shi, H., et al., 1999).
In an extreme form of neurodegenerative genetic disease, familial dysautonomia (FD), the development and survival of neurons (e.g. sensory, sympathetic, parasympathetic) are seriously impaired (Mezey, E., et al., 2003). Delta-T3 increases the IKBKAP gene transcription 3.5-fold, and all tocotrienols increase the IKAP transcripts and proteins (delta-T3 and gamma-T3 producing more than beta-T3 and alpha-T3) as much as 6-fold (Anderson, S., et al., 2003). None of the tocopherols have any effect.
Tocotrienols have been shown to reverse nerve damage and repair, genetic disposition, acute brain damage, glumate induced damage, chronic nerve/brain damage, Alzheimer's, Parkinson's, and Huntington's.
Statin Drugs
Statin drugs are known to decrease isoprenoid pool (IP) products, including intermediate and distal metabolites of CoQ10, dolichol, heme, protein synthesis, and cholesterol (Goldstein, J. L. and M. S. Brown, 1990).
Topical Applications
The skin is an unique site for tocotrienols for both topical and dietary tocotrienol application (Traber, M., et. al, 1998; Ikeda, S., et al., 2003). Tocotrienols protect UV-induced erythema and also prevent the loss of skin vitamin E (Weber, C., et al., 1997; Traber, M., et al., 1997).
Immune System
Dietary tocotrienols given to immunodeficient mice prolonged their survival, presumably via an immune system boost (Tan, B., 1992). Dietary tocotrienols increased immunoglobulin (IgA, IgG and IgM) in rat spleen and MLN lymphocytes where the extent was generally more marked in the T3 group than the alpha-T1 group (Gu, J., et al., 1997; Kaku, S., et al., 1999). Compositionally, C-5 unsubstituted tocotrienols, composed of delta-T3 and gamma-T3, accounted for 75% of the tocols used in these cited studies.
Bone Mineralization
It is known that tocotrienols prevent the loss of bone mineral density, and improve the bone calcium content of growing male and female, however, alpha-T1 supplementation does not improve the mineralization of bone in female rats (Ima-Nirwana, S., et al., 2000; Norazlina, M., et al., 2002; Norazlina, M., et al., 2007).
Hypertension
Gamma-T3 has been shown to prevent the development of increased blood pressure in spontaneous hypertensive rats (SHR) and that the lowest dose of 15 mg/kg feed (approximately translating to 75 mg T3/day for humans) was best in preventing hypertension (Newaz, M. and N. Nawal, 1999). Gamma-T3 is also shown to be a sodium excreting agent, as well as, increasing endothelial nitric oxide synthase (NOS) activity to treat essential hypertension (Igarashi, O., et al., 2003; Newaz, M., et al., 2003). The water-soluble metabolite, γ-CEHC (i.e., chromanol ring without the farnesol tail; see FIG. 2) is the same metabolite for gamma-T3 and for gamma-T1. Such a metabolite has also been identified for alpha-T1, as α-CEHC. Accordingly, the metabolite for delta-T3 and delta-T1, is δ-CEHC.
Cholesterol Biosynthesis
Some 80% of cholesterol in the human body is endogenously produced in the liver, and the remaining 20% from dietary sources. Physiological studies show that cholesterol biosynthesis is nocturnal when dietary intake is at its lowest. When statin is taken in the evening versus morning, lipids drop about 10% more (Wallace, A., et al., 2003). Tocotrienols taken with food more than double their absorption and their maximum concentrations peak 4-6 hours after the supplementation (Yap, S., et al., 2001; Fairus, S., et al., 2003).